Our immune system functions as a "sensor", acting to identify "alien" molecules and organisms such as infectious agents and to mount attacks upon them. If we could "read" immune responses in such a way that they could be linked to specific disease states, a diagnostic tool of extraordinary utility would result. Furthermore, for disease states that are brought about or exacerbated by an immune response, if one could rapidly identify the offending antibodies and/or T-cells, and identify neutralizing molecules specific for them, a revolution in the treatment of these diseases would result. Then it would be possible to specifically interdict responses to specific antigens. The proposed study will begin by attempting to identify antibodies that are unique to Alzheimer's disease (AD), and compare them with normal control individuals, and individuals with Parkinson's disease (PD), which will serve as a "neurodegeneration control group". Because AD patients exhibit neurodegeneration in several rain regions, and neurodegeneration is associated with immune system activation, and a number of antibodies have been detected in the blood of AD and PD patients that differ somewhat in amounts compared to normal individuals, there may well be numerous antibodies in the serum of AD patients that are specific to the disease, which can give rise to lead candidate drugs for the treatment of the disease. The screening tool that we have developed involves a peptoid microarray, consisting of thousands of 8-mer peptoids. Peptoids are oligo-N-substituted glycines (i.e., the side chain is attached to the main chain nitrogen rather than the alpha-carbon). This renders them immune to proteases and far more cell-permeable than peptides. However, peptoids retain the binding characteristics of peptides. We have three specific aims: (1) identify peptoids that accurately discriminate antibodies in the serum of AD patients;(2) identify the specific peptoids that capture the "informative" AD-related IgG and/or IgM antibodies;and (3) using the "informative" peptoids, we will identify the AD-related antibodies. With this knowledge, future experiments can be undertaken to determine whether the informative peptoids can be used to neutralize the antibodies in model systems and thereby show potential as novel AD medications. PUBLIC HEALTH RELEVANCE: The goal of this project is to begin the process of developing lead candidate drugs for the treatment of Alzheimer's disease (AD). Antibodies to the amyloid-beta peptide have been identified in the blood of AD patients, and this antibody has been used for therapeutic purposes. We will begin by using a novel screening tool, a peptoid array, to look for and identify antibodies in the blood of AD patients that are unique to the disease. This study begins the pathway that provides a mechanism to: (1) identify auto-antibodies in serum that are associated with AD without foreknowledge of the molecular mechanism of the disease, and (2) isolate antigens associated with the disease state. Given the wide range of disease states to which the immune system is known, or is likely to react, this technology could provide a medical diagnostics platform of extraordinary utility and scope. The downstream antigen identification studies could provide new information on the biology of the disease process. Of equal or greater importance, it is likely that some of the "high information content" peptoids capture the antibodies that are causative of the disease, or of disease progression (e.g., antibodies related to brain inflammation). Thus, the capture peptoids are immediate leads for compounds capable of selectively neutralizing these antibodies without generally dampening the overall immune response. A technology for the discovery of highly specific immunomodulatory agents could transform the treatment of AD.